The proposed work evaluates six specific hypotheses examining the relationship between platelet serotonin (5HT) uptake and binding and the clinical course of major depression. The study utilizes a longitudinal design to follow 60 patients who are initiating therapy with nortriptyline and evaluated for changes in platelet serotonin ligand kinetics associated with their clinical antidepressant response. In this proposal, new techniques for measurement of platelet serotonin2 receptor binding, using LSD as a ligand, are combined with previously established methods for kinetically characterizing platelet serotonin uptake and imipramine binding. The work is based on pilot data generated from our own laboratory, which indicates that these measures may potentially assay a patient's individual serotonin response to tricyclic antidepressants, and that relapses in remitted depressed patients withdrawing from medication can be predicted. The proposed careful evaluations of the patients will do four things. First, platelet 5HT uptake will be tested as a bioassay to examine the possibility that the affinity constant (Km) may indicate a minimum effective dose of nortriptyline. Second, we will extend our prior cross-sectional findings that documented disturbances of platelet 5HT uptake in drug-free depressed patients, and examine whether a successful treatment response is associated with a correction of the decreased capacity for 5HT uptake and imipramine binding. Third, the project will combine newly developed LSD binding techniques for measurement of serotonin (5HT2) receptors on platelets to search for chronic adaptive changes associated with the onset of antidepressant response. Fourth, in order to take advantage of our future contact with the patients, we will use these methods to gather preliminary information on the utility of these measures to predict recurrences of illness in patients who have responded to nortriptyline treatment. The design of the study builds on the resources of the NIMH- funded Clinical Research Center (CRC) at the San Diego VAMC as a method for patient identification, treatment and followup. The proposed five-year research plan will enable prospective, longitudinal study for a necessary length of time and number of subjects for classification of the different antidepressant response outcomes.